This is a K01 application by Dr. Adel Driss, a research instructor at MSM. Dr. Driss is establishing himself as a young investigator pursuing research in global health to understand the molecular mechanisms mediating interactions between hemoglobinopathies and Malaria. Although these two diseases overlap in sub-Saharan Africa, the biological interactions between malaria and hemoglobinopathies are poorly understood. Dr. Driss recently returned from Ghana after an eleven-month field study sponsored by a Fogarty Global Health Fellows award to screen microRNA polymorphisms associated with severity of anemia in sickle cell and malaria in Ghana. This collaborative research was conducted between MSM and the University of Ghana (UG). He successfully obtained blood samples and clinical data and conducted preliminary analysis during his fellowship. This K01 award will greatly enhance Dr. Driss' goals of: 1) developing a path to independence in biomedical research; 2) conducting investigations on the role of microRNA's in the pathogenesis of malaria and hemoglobinopathies; 3) applying advanced genomic and proteomic methods to identify and validate biomarkers of malaria severity; and 4) developing global health collaborations between MSM in the USA and UG in West Africa. To achieve these goals, Dr. Driss has assembled a mentoring team consisting of: Dr. Stiles, Professor of Microbiology at MSM, who will provide support through his expertise in immuno- pathogenesis of blood diseases and hemoglobinopathies; Dr. Wilson, Professor of Parasitology at Noguchi Memorial Institute for Medical Research at the UG. Dr. Wilson will provide the necessary onsite support and guidance in the Ghanaian host institution; Dr. Hibbert, Associate Professor and an expert in animal studies relating to the role of nutrition in modulation of various human diseases will provide support for the proposed animal studies; and Dr. Quarshie will provide statistical support. The rationale for the proposed study is that specific host-derived microRNAs (miR-451 and Let-7i) have been associated with protection against the Malaria parasite in individuals with sickle-cell trait. These findings have never been validated in a population- based study. The hypothesis is that malaria severity is associated with alterations in expression of microRNAs linked to the hemoglobinopathy status of the individuals affected. Thus, Dr. Driss proposes 3 aims to (i) correlate miR-451 and Let-7i expression profiles with clinical blood analytical values and heme metabolism in individuals with different sickle cell status; (ii) characterize the role of miR-451 and Let-7i regulation on P. falciparum development in human erythrocytes in vitro and (iii) determine the role of miR-451 and Let-7i in modulation of pathogenesis of malaria and hemoglobinopathies in a sickle cell mouse model. The overall goal is to increase understanding of malaria severity in individuals with hemoglobinopathies and to identify molecular biomarkers that may be used to predict severity risk which can be attractive targets to malaria protection therapies. The experience gained will allow Dr. Driss to successfully compete for an R01 funding.